(a) Field of the Invention
This invention relates to a novel method for preparing 5-Q-[3,4'-bipyridin]-6(1H)-one where Q is cyano or carbamyl, a novel intermediate used therein and its preparation, and to the use of said novel intermediate or salt in a cardiotonic composition or method for increasing cardiac contractility.
(b) Description of the Prior Art
Lesher and Opalka U.S. Pat. No. 4,004,012, issued Jan. 18, 1977, shows two methods of preparing 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitriles and conversion by hydrolysis to the corresponding nicotinamides, one method of preparing 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinamides, and, in turn, the conversion of the nicotinamides to the corresponding 3-amino compounds. These methods are presented structurally in columns 3 and 4 of U.S. Pat. No. 4,004,012. Two methods are disclosed for preparing 1,2-dihydro-2-oxo-5-(pyridinyl)-nicotinonitriles (III in patent), i.e., (1) by reacting .alpha.-(pyridinyl)-.beta.-(R.sub.1 R.sub.2 N)acrolein (II in patent) with .alpha.-cyanoacetamide in the presence of a basic condensing agent, preferably an alkali lower-alkoxide, e.g., sodium methoxide or sodium ethoxide, in a lower-alkanol, e.g., methanol or ethanol; and, (2) by heating .alpha.-(pyridinyl)-malonaldehyde with .alpha.-cyanoacetamide in the presence of a catalytic condensing agent, preferably morpholine or piperidine and/or its acetate. As shown in Example A-1 in the paragraph common to columns 9 and 10 of U.S. Pat. No. 4,004,012, the product in method (1) is collected as its sodium salt, recrystallized and then converted by treatment with hydrochloric acid to 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitrile. Also disclosed is a method of preparing 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinamides by reacting .alpha.-(pyridinyl)-.beta.-(R.sub.1 R.sub.2 N)acrolein with malonamide.
A recently published abstract ["Current Abstracts of Chemistry", Vol. 74, Issue 814, Item 285573, 1979] of a Polish publication [Nantkanomirski and Kaczmarek, Polish J. Pharmacol. Pharmacy 30(5), 707-12 (1978)] shows, inter alia, the reaction of 3-dimethylamino-2-(4-pyridinyl)acrolein [same as .beta.-(dimethylamino)-.alpha.-(4-pyridinyl)acrolein] with malononitrile in the presence of sodium methoxide in methanol to produce 2-methoxy-5-(4-pyridinyl)nicotinonitrile.
Arnold [Coll. Czech. Chem. Comm. 28, 863-868 (1963)] shows the preparation of .beta.-dimethylamino-.alpha.-(4-pyridinyl)acrolein by three different methods: (a) formylation of 4-picoline with dimethylformamide and phosphorus oxychloride; (b) formylation of 4-picoline with dimethylformamide and phosgene in chloroform; and, (c) formylation of 4-(2-dimethylaminovinyl)pyridine with dimethylformamide and phosgene in chloroform.